HIV encephalitis (HIVE) is observed at autopsy in 20-30% of HIV infected individuals dying with AIDS [1], [2], [3], [4], [5]. The host and viral characteristics which predispose an individual to HIVE and its clinical correlate, HIV associated dementia (HAD), have yet to be described. Severe HIVE develops in later stages of disease, suggesting that loss of immune competence is one factor favoring overt HIV infection of brain. The tropism of HIV strains within an individual may be important as well. CNS lesions of HIVE consist of HIV infected macrophages, suggesting that monocyte/macrophage (M/M) tropic strains of HIV mediate CNS disease. To investigate whether (M/M) tropic strains of HIV could be detected in the peripheral blood and if their presence indicated a predisposition to HIV CNS disease, monocytes from infected donors were cultured in vitro. M/M tropic strains of HIV were recovered from most individuals (63%) and in all (5) patients with dementia to date. The first hypothesis proposed is that HIV infected individuals, who show a higher frequency of HIV infected M/M, are more likely to develop mild neurocognitive disorder (MND) and overt HAD as measured by higher impairment ratings on neuropsychological testing and reduced volume of gray matter in quantitated MR image analysis. Quantitation of infected M/M will be done by a) PCR for HIV DNA in isolated M/M prior to culture, b) measurement of HIV p24 produced, and c) frequency of infectious centers. The second hypothesis is that the immune system, specifically CD8 T-cells, can inhibit HIV production [6],[7] and thus may influence development of HIVE. We propose that peripheral CD8 antiHIV T-cells (with or without CD4 T-cell activity to HIV) restrict overt infection of the CNS and that loss of CD8 control will lead to overt infection of the CNS. CD8 T-cell activity will be measured by suppression of HIV expression in autologous M/M and CD4 T-cells. Loss of CD8 anti HIV activity and greater levels of HIV in M/M is predicted to increase likelihood of MND and HAD. Analysis of M/M tropic virus and CD8 T-cell activity in 180 HIV infected individuals will be done at yearly intervals in medically asymptomatic individuals and every 6 months in those with AIDS. This group is selected so that at least 60 individuals will be autopsied in 5 years. Longitudinal neuropsychological and (eventually) neuropathologic data assessing levels of HIV in brain will be related to quantitation of infected M/M and CD8 anti HIV activity. In collaboration with Dr. Wong-Staal, strains of HIV isolated in peripheral blood M/M will be compared to those isolated from following autopsy. The results of this study should clarify the importance of macrophage tropic strains in infection of the CNS and the contribution of CD4 and CD8 T-cell responses in controlling HIV mediated CNS disease.